The clinical use of antibiotics in the 20th century has substantially decreased morbidity from bacterial infections. The early success of penicillin was extended by various sulfonamide drugs developed in the 1930s, and subsequently by a “golden” period of discovery, between 1945 and 1970, during which a wide array of highly effective agents are discovered and developed (Chopra, I., et al., “The Search for Antimicrobial Agents Effective against Bacteria Resistant to Multiple Antibiotics” Antimicrobial Agents and Chemotherapy, 1997, 41:497-503).
However, since the 1980s the introduction of new antibiotics has slowed, and, concurrently, there has been an alarming increase in bacterial resistance to existing agents that now constitutes a serious threat to public health (Brown, A. G. “Discovery and Development of New β-Lactam Antibiotics” Pure & Appl. Chem., 1987, 59:475-484). Hospitals, nursing homes and infant day care centers have become breeding grounds for the most tenacious drug-resistant pathogens (“Frontiers in Biotechnology” Science, 1994, 264:359-393). There has been an alarming rise in drug resistant staphylococci, enterococci, streptococci, and pneumococci infections, and a rise in tuberculosis, influenza and sepsis.
The problem of bacterial drug resistance has reached a crisis level such that successful treatment of antibiotic-resistant infections in hospitals and health care centers can no longer be taken for granted. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are becoming particularly difficult to treat with conventional antibiotics such as penicillin, leading to a sharp rise in clinical complications and deaths. The need for new antibacterial agents and protocols for treating MRSA infections is becoming extremely serious.
A novel family of lipophilic N-thiolated β-lactams that are effective growth inhibitors of MRSA and Bacillus species has been reported (U.S. Pat. No. 6,473,015 B1 to Turos et al. and U.S. Pat. No. 6,946,458 B2 to Turos; see also. Ren, X. F. et al., J. Org. Chem. 60 (1995), p. 4980; Ren, X. F. et al., J. Org. Chem. 63 (1998), p. 8898; E. Turos, E. et al., Tetrahedron 56 (2000), p. 5571; E. Turos, E. et al., Bioorg. Med. Chem. Lett. 12 (2002), p. 2229; C. Coates, C. et al., Bioorg. Med. Chem. 11 (2003), p. 193; Long, E. et al., Bioorg. Med. Chem. 11 (2003), p. 1859; Kazi, A. et al., Biochem. Pharmacol. 67 (2004), p. 365; Turos, E. et al., J. Bioorg. Med. Chem. Lett. 2006 (in press)). The mode of action and structure-activity profiles differ dramatically from those of traditional β-lactams. (See generally Chemistry and Biology of β-Lactam Antibiotics; Morin, R. B., Gorman, M.; Eds.; Academic Press: New York, 1982; Vols 1-3.) Investigations have shown that these β-lactam compounds can carry a wide range of substituents at the C3 and C4 centers; however, the N-organothio substituent is necessary for microbiological activity. (E. Turos, E. et al., Bioorg. Med. Chem. 13 (2005), p. 6289.) The mechanism of action is under investigation but appears to depend on the ability of the compounds to transfer the organothio moiety onto a cellular thiol. This suggests that the role of the lactam ring is to provide a structural framework for the delivery of the thiol moiety and may not be absolutely required for the activity. To probe this possibility, and to expand on the structural diversity of anti-MRSA compounds available for clinical development, we decided to examine oxazolidinones as potential antibacterially active organothio carriers. Oxazolidinones are already recognized for their favorable pharmacological properties and are the only new class of antibacterial drugs introduced into clinical use in the last three decades. (Brickner, S., J. Curr. Pharm. Des. 2 (1996), p. 175; Phillips, O. A., Curr. Opin. Invest. Drugs 4 (2003), p. 117; S. J. Brickner, S. J. et al., J. Med. Chem. 39 (1996), p. 673.)
Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are becoming extremely difficult to treat with conventional antibiotics, leading to a sharp rise in clinical complications (Binder, S. et al. Science, 1999, 284:1311). The need for new antibiotics and protocols for treating MRSA infections is extremely serious.
There is a clear need for new antibacterial agents to combat pathogenic bacteria that have become resistant to current antibiotics. Towards this end, a novel class of derivatized, N-thiolated-2-Oxazolidones have been developed in the present invention, that exhibit strong antibacterial activity against a wide variety of species and strains, including methicillin-resistant Staphylococcus aureus. 